Michael Wittlinger

Distribution of immune cells in head and neck cancer: CD8+ T-cells and CD20+B-cells in metastatic lymph nodes are associated with favourable outcome in patients with oro- and hypopharyngeal carcinoma

BackgroundTumour infiltrating lymphocytes (TIL) are generally considered to represent a host immune response directed against tumour antigens. TIL are also increasingly recognised as possible prognostic parameters. However, the effects observed are variable indicating that results cannot be extrapolated from type of tumour to another. Moreover, it has been suggested that primary solid tumours may be ignored by the immune system and that a meaningful immune response is only mounted in regional lymph nodes.MethodsWe have examined the local distribution of immune cells in tumour-related compartments in head and neck squamous cell carcinomas (HNSCC). In a second step, the prognostic impact of these cells on disease-free survival (DFS) was analysed. A total of 198 tissue cores from 33 patients were evaluated using tissue mircroarray technique and immunohistochemistry. Tumour-infiltrating immune cells were identified using antibodies specific for CD3, CD8, GranzymeB, FoxP3, CD20 and CD68 and quantified using an image analysis system.ResultsWe demonstrate a relative expansion of FoxP3+ regulatory T-cells (Treg) and of cytotoxic T-cells among tumour infitrating T-cells. We also show that intratumoural CD20+ B-cells are significantly more frequent in metastatic deposits than in primary tumours. Furthermore, we observed a reduced number of peritumoural CD8+ T-cells in metastatic lymph nodes as compared to univolved regional nodes suggesting a local down-modulation of cellular immunity. All other immune cells did not show significant alterations in distribution. We did not observe an association of tumour infiltrating immune cells at the primary site with outcome. However, increased numbers of intraepithelial CD8+ TIL in metastatic tumours as well as large numbers of peritumoural B-cells in lymph node metastases were associated with favourable outcome. Unexpectedly, no effect on patient outcome was observed for Treg in any compartment.ConclusionOur results suggest that alterations in lymphocyte distribution in regional lymph nodes rather than at the primary tumour site may be relevant for patient prognosis. Moreover, we demonstrate that in addition to cellular immunity humoral immune responses may be clinically relevant in anti-tumour immunity.

Expression of TIP60 (tat‐interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment‐specific outcome of localised invasive bladder cancer

Whats known on the subject? and What does the study add?

Quadrimodal treatment of high-risk T1 and T2 bladder cancer: Transurethral tumor resection followed by concurrent radiochemotherapy and regional deep hyperthermia

BACKGROUND AND PURPOSE To assess the safety and effectiveness of treating high-risk T1 and T2 bladder cancer with transurethral resection (TUR-BT) followed by radiochemotherapy (RCT) combined with regional deep hyperthermia (RHT). MATERIAL AND METHODS Between 2003 and 2007, 45 patients were enrolled. After TUR-BT patients received radiotherapy (RT) of the bladder and regional lymph nodes with 50.4 Gy, and a boost to the bladder of 5.4-9 Gy. RCT was applied to 43/45 patients. RHT was administered once weekly. Response was re-evaluated 6 weeks after RT by restaging-TUR. Toxicity was graded with the CTCAE, version 3.0. QoL was evaluated by a dedicated questionnaire. RESULTS The median follow-up was 34 months (range 12-60). The median number of hyperthermia treatments was 5 (range 1-7). Acute toxicity grades 3 and 4 occurred in 20% (9/45) and 9% (4/45), respectively. Late toxicity grades 3/4 were seen in 24% (11/45). Complete response rate was 96% (43/45). Local recurrence-free survival was 85%, overall survival was 80%, disease-specific survival was 88%, metastasis-free survival was 89%, and the bladder-preserving rate was 96% (43/45) at 3 years. Eighty percent (24/30) were at least mostly satisfied with their bladder function. CONCLUSIONS The quadrimodal treatment was feasible and well tolerated. Local control and bladder-preserving rates were encouraging.

Radiochemotherapy for bladder cancer.

Standard treatment for muscle-invasive bladder cancer is cystectomy. Multimodality treatment, including transurethral resection of the bladder tumour, radiation therapy, chemotherapy and deep regional hyperthermia, has been shown to produce survival rates comparable with those of cystectomy. With these programmes, cystectomy has been reserved for patients with incomplete response or local relapse. During the past two decades, organ preservation by multimodality treatment has been investigated in prospective series from single centres and co-operative groups, with more than 1000 patients included. Five-year overall survival rates in the range of 50-60% have been reported, and about three-quarters of the surviving patients maintained their bladder. Clinical criteria helpful in determining patients for bladder preservation include such variables as small tumour size (<5 cm), early tumour stage, a visibly and microscopically complete transurethral resection, absence of ureteral obstruction, and no evidence of pelvic lymph node metastases. On multivariate analysis, the completeness of transurethral resection of a bladder tumour was found to be one of the strongest prognostic factors for overall survival. Patients at greater risk of new tumour development after initial complete response are those with multifocal disease and extensive associated carcinoma in situ at presentation. Close co-ordination among all disciplines is required to achieve optimal results. Future investigations will focus on optimising radiation techniques, including all possibilities of radiosensitisation (e.g. concurrent radiochemotherapy, deep regional hyperthermia), and incorporating more effective systemic chemotherapy, and the proper selection of patients based on predictive molecular makers.

SURVIVIN EXPRESSION AS A PREDICTIVE MARKER FOR LOCAL CONTROL IN PATIENTS WITH HIGH-RISK T1 BLADDER CANCER TREATED WITH TRANSURETHRAL RESECTION AND RADIOCHEMOTHERAPY

PURPOSE The objectives of this study were to investigate the expression of survivin in tumor samples from patients with high-risk T1 bladder cancer and to correlate its expression with clinicopathologic features as well as clinical outcomes after initial transurethral resection (TURBT) followed by radiotherapy (RT) or radiochemotherapy (RCT). METHODS AND MATERIALS Survivin protein expression was evaluated by immunohistochemistry on tumor specimen (n = 48) from the initial TURBT, and was correlated with clinical and histopathologic characteristics as well as with 5-year rates of local failure, tumor progression, and death from urothelial cancer after primary bladder sparring treatment with RT/RCT. RESULTS Survivin was not expressed in normal bladder urothelium but was overexpressed in 67% of T1 tumors. No association between survivin expression and clinicopathologic factors (age, gender, grading, multifocality, associated carcinoma in situ) could be shown. With a median follow-up of 27 months (range, 3-140 months), elevated survivin expression was significantly associated with an increased probability of local failure after TURBT and RCT/RT (p = 0.003). There was also a clear trend toward a higher risk of tumor progression (p = 0.07) and lower disease-specific survival (p = 0.10). CONCLUSIONS High survivin expression is a marker of tumor aggressiveness and may help to identify a subgroup of patients with T1 bladder cancer at a high risk for recurrence when treated with primary organ-sparing approaches such as TURBT and RCT.

Treatment Options for High-Risk T1 Bladder Cancer

Purpose:To review the standards and new developments in diagnosis and management of high-risk T1 bladder cancer with emphasis on the role of radiotherapy (RT) and radiochemotherapy (RCT).Material and Methods:A systematic review of the literature on developments in diagnosis and management of high-risk T1 bladder cancer was performed.Results:First transurethral resection (TUR), as radical as safely possible, supported by fluorescence cystoscopy, shows higher detection and decreased recurrence rates. An immediate single postoperative instillation with a chemotherapeutic drug reduces the relative risk of recurrence by 40%. A second TUR is recommended to assess residual tumor. For adjuvant intravesical therapy, bacille Calmette-Guérin (BCG) demonstrated the highest efficacy. Early cystectomy should be reserved for selected patients. A recent phase III trial comparing RT versus conservative treatment in T1 G3 tumors could not show any advantage for RT. Data from Erlangen, Germany, using combined RCT in 80% of the patients, compare favorably with most of the contemporary BCG series.Conclusion:Results of intravesical therapy are still unsatisfying and early cystectomy is associated with morbidity and mortality. RT alone proved not superior to other conservative treatment strategies. However, data on RCT are promising and demonstrate an alternative to intravesical therapy and radical cystectomy.Ziel:Dieser Artikel gibt eine Übersicht über die Standards und neuen Entwicklungen in der Diagnostik und Therapie des oberflächlichen „high-risk“-Harnblasenkarzinoms mit Schwerpunkt auf der Rolle der Radiotherapie (RT) bzw. Radiochemotherapie (RCT).Material und Methodik:Es wurde eine systematische Literatursuche hinsichtlich der aktuellen Entwicklungen in der Diagnostik und Therapie des oberflächlichen „high-risk“-Harnblasenkarzinoms durchgeführt.Ergebnisse:Die Einführung der fluoreszenzgestützten transurethralen Resektion (TUR) und eine anschließende zweite TUR erhöhen die Diagnosesicherheit und verbessern die Ergebnisse. Zusätzlich kann eine postoperative Chemoinstillation nach der ersten TUR die Rezidivrate um 40% senken. Als Adjuvans zeigt die Bacillus-Calmette-Guérin-(BCG-)Instillation die besten Resultate. Die sofortige Zystektomie soll daher ausgewählten Patienten vorbehalten bleiben. Eine Phase-III-Studie für T1G3-Tumoren, welche die RT mit konservativen Behandlungsstrategien verglich, erbrachte keinen Vorteil für die RT. Daten einer Studie aus Erlangen, in der 80% der Patienten mit „high-risk“-T1-Tumoren eine RCT erhielten, sind mit den besten BCG-Serien vergleichbar.Schlussfolgerung:Die Entscheidung zwischen einem primär organerhaltenden Therapieansatz und einer frühzeitigen Zystektomie bleibt schwierig. Die alleinige RT zeigt sich im randomisierten Vergleich den Instillationstherapien nicht überlegen. Die Daten zur RCT sind vielversprechend und rechtfertigen diese Therapie als Alternative zur intravesikalen Therapie bzw. frühen Zystektomie.

Treatment options for high-risk T1 bladder cancer: status quo and future perspectives of radiochemotherapy.

Purpose:To review the standards and new developments in diagnosis and management of high-risk T1 bladder cancer with emphasis on the role of radiotherapy (RT) and radiochemotherapy (RCT).Material and Methods:A systematic review of the literature on developments in diagnosis and management of high-risk T1 bladder cancer was performed.Results:First transurethral resection (TUR), as radical as safely possible, supported by fluorescence cystoscopy, shows higher detection and decreased recurrence rates. An immediate single postoperative instillation with a chemotherapeutic drug reduces the relative risk of recurrence by 40%. A second TUR is recommended to assess residual tumor. For adjuvant intravesical therapy, bacille Calmette-Guérin (BCG) demonstrated the highest efficacy. Early cystectomy should be reserved for selected patients. A recent phase III trial comparing RT versus conservative treatment in T1 G3 tumors could not show any advantage for RT. Data from Erlangen, Germany, using combined RCT in 80% of the patients, compare favorably with most of the contemporary BCG series.Conclusion:Results of intravesical therapy are still unsatisfying and early cystectomy is associated with morbidity and mortality. RT alone proved not superior to other conservative treatment strategies. However, data on RCT are promising and demonstrate an alternative to intravesical therapy and radical cystectomy.Ziel:Dieser Artikel gibt eine Übersicht über die Standards und neuen Entwicklungen in der Diagnostik und Therapie des oberflächlichen „high-risk“-Harnblasenkarzinoms mit Schwerpunkt auf der Rolle der Radiotherapie (RT) bzw. Radiochemotherapie (RCT).Material und Methodik:Es wurde eine systematische Literatursuche hinsichtlich der aktuellen Entwicklungen in der Diagnostik und Therapie des oberflächlichen „high-risk“-Harnblasenkarzinoms durchgeführt.Ergebnisse:Die Einführung der fluoreszenzgestützten transurethralen Resektion (TUR) und eine anschließende zweite TUR erhöhen die Diagnosesicherheit und verbessern die Ergebnisse. Zusätzlich kann eine postoperative Chemoinstillation nach der ersten TUR die Rezidivrate um 40% senken. Als Adjuvans zeigt die Bacillus-Calmette-Guérin-(BCG-)Instillation die besten Resultate. Die sofortige Zystektomie soll daher ausgewählten Patienten vorbehalten bleiben. Eine Phase-III-Studie für T1G3-Tumoren, welche die RT mit konservativen Behandlungsstrategien verglich, erbrachte keinen Vorteil für die RT. Daten einer Studie aus Erlangen, in der 80% der Patienten mit „high-risk“-T1-Tumoren eine RCT erhielten, sind mit den besten BCG-Serien vergleichbar.Schlussfolgerung:Die Entscheidung zwischen einem primär organerhaltenden Therapieansatz und einer frühzeitigen Zystektomie bleibt schwierig. Die alleinige RT zeigt sich im randomisierten Vergleich den Instillationstherapien nicht überlegen. Die Daten zur RCT sind vielversprechend und rechtfertigen diese Therapie als Alternative zur intravesikalen Therapie bzw. frühen Zystektomie.

Treatment Options for High-Risk T1 Bladder Cancer@@@Behandlungsoptionen für T1-Harnblasenkarzinome mit hohem Risiko. Aktueller Stand und Zukunftsperspektiven der Radiochemotherapie: Status Quo and Future Perspectives of Radiochemotherapy

Purpose:To review the standards and new developments in diagnosis and management of high-risk T1 bladder cancer with emphasis on the role of radiotherapy (RT) and radiochemotherapy (RCT).Material and Methods:A systematic review of the literature on developments in diagnosis and management of high-risk T1 bladder cancer was performed.Results:First transurethral resection (TUR), as radical as safely possible, supported by fluorescence cystoscopy, shows higher detection and decreased recurrence rates. An immediate single postoperative instillation with a chemotherapeutic drug reduces the relative risk of recurrence by 40%. A second TUR is recommended to assess residual tumor. For adjuvant intravesical therapy, bacille Calmette-Guérin (BCG) demonstrated the highest efficacy. Early cystectomy should be reserved for selected patients. A recent phase III trial comparing RT versus conservative treatment in T1 G3 tumors could not show any advantage for RT. Data from Erlangen, Germany, using combined RCT in 80% of the patients, compare favorably with most of the contemporary BCG series.Conclusion:Results of intravesical therapy are still unsatisfying and early cystectomy is associated with morbidity and mortality. RT alone proved not superior to other conservative treatment strategies. However, data on RCT are promising and demonstrate an alternative to intravesical therapy and radical cystectomy.Ziel:Dieser Artikel gibt eine Übersicht über die Standards und neuen Entwicklungen in der Diagnostik und Therapie des oberflächlichen „high-risk“-Harnblasenkarzinoms mit Schwerpunkt auf der Rolle der Radiotherapie (RT) bzw. Radiochemotherapie (RCT).Material und Methodik:Es wurde eine systematische Literatursuche hinsichtlich der aktuellen Entwicklungen in der Diagnostik und Therapie des oberflächlichen „high-risk“-Harnblasenkarzinoms durchgeführt.Ergebnisse:Die Einführung der fluoreszenzgestützten transurethralen Resektion (TUR) und eine anschließende zweite TUR erhöhen die Diagnosesicherheit und verbessern die Ergebnisse. Zusätzlich kann eine postoperative Chemoinstillation nach der ersten TUR die Rezidivrate um 40% senken. Als Adjuvans zeigt die Bacillus-Calmette-Guérin-(BCG-)Instillation die besten Resultate. Die sofortige Zystektomie soll daher ausgewählten Patienten vorbehalten bleiben. Eine Phase-III-Studie für T1G3-Tumoren, welche die RT mit konservativen Behandlungsstrategien verglich, erbrachte keinen Vorteil für die RT. Daten einer Studie aus Erlangen, in der 80% der Patienten mit „high-risk“-T1-Tumoren eine RCT erhielten, sind mit den besten BCG-Serien vergleichbar.Schlussfolgerung:Die Entscheidung zwischen einem primär organerhaltenden Therapieansatz und einer frühzeitigen Zystektomie bleibt schwierig. Die alleinige RT zeigt sich im randomisierten Vergleich den Instillationstherapien nicht überlegen. Die Daten zur RCT sind vielversprechend und rechtfertigen diese Therapie als Alternative zur intravesikalen Therapie bzw. frühen Zystektomie.